KDM6A was first reported in relation to X-linked dominant Kabuki syndrome 2 (KS2) in 2012 (Lederer D et al., PMID: 22197486). Features of KS2 include neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, motor delay, intellectual disability, microcephaly, congenital heart anomalies, palate defects, renal malformations, hearing loss, recurrent infections, joint hypermobility, and gastroesophageal reflux (Faundes V et al., PMID: 33674768). While Kabuki syndrome 1 (KS1) is characterized by distinct facial dysmorphism, facial phenotypes of patients with KS2 and KDM6A variants are highly variable. At least 13 unique variants (missense, nonsense, small insertion, splice site, small deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data.
Summary of Case Level Data: 19.6 Variants in this gene have been reported in at least 13 probands in 6 publications (PMID: 22197486, PMID: 23076834, PMID: 24664873, PMID: 23913813, PMID: 30509212, PMID: 27302555).
Summary of Experimental Data: 4.5 This gene-disease association is supported by multiple animal and cell culture models (PMID: 29073101, PMID: 25972376, PMID: 26431949, PMID: 34126175). Van Laarhoven PM et al., (2015) knocked down the expression of KDM6A orthologs in zebrafish (kdm6a and kdm6al). Morphants exhibited severe abnormalities in all tissues examined, presenting with craniofacial phenotypes and defects in heart development. Shpargel KB et al., (2017) demonstrated that mice carrying neural crest deletion of UTX (KDM6A) display craniofacial dysmorphism, cardiac defects, and postnatal growth retardation. Cook KD, et al., (2015) showed UTX-deficient T cells have decreased expression of interleukin-6 receptor-α and identified a critical link between UTX in T cells and immunity to infection.
In summary, there is definitive evidence to support the relationship between the KDM6A gene and X-linked dominant Kabuki syndrome 2, however, the variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 are still not fully understood.
This classification was approved by the ClinGen SCID-CID GCEP on the meeting date July 15, 2021 (SOP Version 8).
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